IL43749A

IL43749A - Cyclopropylmethylamine derivatives of n-containing heterocyclic compounds their production and pharmaceutical compositions containing them

Info

Publication number: IL43749A
Application number: IL43749A
Authority: IL
Original assignee: Science Union & Cie
Priority date: 1972-12-28
Filing date: 1973-12-04
Publication date: 1977-06-30
Also published as: AR211914A1; AU6340073A; ATA1089973A; JPS5335949B2; US3988464A; CS186258B2; JPS5422978B2; ES421879A1; DK145574C; SU591136A3; JPS504084A; AT333272B; FR2212143B1; CH592641A5; SE388420B; JPS544955B2; HU169273B; ZA739694B; BE809179A; JPS5359665A

Description

heterocyclic The present invention relates to and more particularly to cyclopropylmethylaniines substituted by a heterocyclic to their preparation and to pharmaceutical compositions containing The present invention provides substituted cyclopropylmethylaniines of the general formula I wherein and which are the same or each represents a hydrogen a lower alkyl radical or a cyclopropyl radical optionally substituted with one or more lower alkyl radicals is a lower alkyl radical for lined is a hydrogen atom or a lower alkyl radical meanings of A is an oxyge a sulphur atom or an stituents radical is 0 1 or and is 2 or la The present invention also provides acid addition salts of these compounds with a mineral or organic The term is used herein to designate an radical having from 1 to 6 carbon and Rg are the carbon atom which bears these tuents is and thus the compounds may be resolved into their optical antipodes The resolution may be carried out reacting a compound of general formula I vdth an optically active for tartaric acid or resulting optically active salt is transformed into the optically active base by adding a strong mineral or organic or a strong mineral The resolution may be also effected at another step either by using a previously resolved material II or by resolving the intermediate ureas Compounds of the general formula I wherein the heterocyclic radical is oxygen n sulphur n n 5 n 5 oxygen n 4 5 6 oxygen n 2 are particularly S Patent Specification No 2 899 426 discloses a new method for the synthesis of derivatives and of their acid addition Although this broad definition also covers the of formula I of the present invention none of these compounds has been specifically mentioned in the above Preferred compounds of the present invention are the cyclopropylmethylamines of the formula wherein and are the same or different and are each a hydrogen a lower radical or cyclopropyl radical A is an oxygen a sulphur atom or an imino radical and n is 0 1 or 2a The compounds of the present invention have useful pharmacological therapeutical In they influence the cardiovascular They a depressant action on the central nervous which may result in analgesic action antipsychotic The compounds of the invention are used principally as The present invention also provides a pharmaceutical preparation comprising as active ingredient at least one compound of general in admixture or conjunction with a pharmaceutically suitable The pharmaceutical preparation may be in any form suitable for oral parenteral sublingual percutaneous or rectal More particularly it may be in the form of tablets coated tablets soft gelatin capsules ampules phials multidose phials capsules syrups drops sublingual tablets lotions solutions or suppositories The usual dosage may vary depending of the theraputical the age of the patient and the method of It range from 1 mg to 5 dosage The daily dosage may range from 1 mg to 30 The preferred unit dosage ranges from 2 to 4 The pharmaceutical compositions including as active ingredient one or more compounds of general formula I are prepared according to methods known in the pharmaceutical The invention also provides a process for the preparation of the compounds of general formula I which comprises condensing a of general formula II wherein R1 and are defined as ahove either with a having the general formula ΙΠ w ere n is an or sulphur Hal i3 a chlorine or bromine atom i and is an integer of from 2 to 4 to form a disubstituted urea or thiourea of general IV wherein the substituents and Hal are defined as previously which is cyclised by heating into a compound of general formula I wherein is an oxygen or sulphur n is 1 or 2 and and are defined as previously state if salifying this compound by adding a mineral or organic or resolving it by means of an optically active with a cyclic isothiourea of the formula V wherein n is 1 or 2 to form a compound of general formula I wherein R3 as if salifying this compound by adding a mineral or organic The condensation between a of general formula I with an isocyanate or isothiocyanate of general ormula III is preferably carried The most preferred solvents are isopropyl ether or tetrahydrofuran as an triethylamine as a trialiylamine toluene or benzene as an ethyl acetate as a lower pentane or cyclohexane as a or a mixture of two or more The cyclisation of the or urea of general formula occurs by preferably in an aqueous This dehydrohalogenation may be effected in the presence or in absence of a basic agent in order to bind any hydrohalic acid formed during the The basic agent may be a mineral basic for an alkali metal carbonate or an alkali metal an oxide or or a basic salt of It may be also an organic for a dialkyl a or The cyclisation is preferably effected by warming at a temperature of from to depending of the nature of the solvent and of the molecule to be this operation is effected at about The condensation between of general formula II and a cyclic isothiourea of formula V occurs preferably by heating from to in a polar Examples of suitable polar solvents are dimethyl dimethyl hexaphosphorotriamide and The present invention also provides another process for producing pounds of general formula I A represents an oxygen compounds having the formula in which the definition of the are the same as which I wherein the substituents and are defined as above with an halogeno formate of the formula Hal 0 Ar wherein Hal is fluorine or chlorine and Ar is a phenyl radical or a radical substituted by one or more radicals of electrophilic character in order to produce a carbamate of the formula VI wherein Ar and are defined as above condensing the carbamate of formula VI with an aminoalkanol of formula VII OH wherein is an integer from 2 to 4 to get a hydroxyalkyl urea of formula VIII wherein the definitions of the substituents remain unchanged submitting the hydroalkyl urea of formula VIII to the action of an halogenating agent to form the corresponding urea of formula IV N C IV 2 and cyclising the latter by warming to produce a compound of general formula I wherein A is an oxygen This process is also defined with the following features the aryl halogenoformate is preferably a chloride the aryl radical is preferably a phenyl a nitro phenyl a dinitro phenyl radical or a chloro nitro phenyl radical the condensation with the aryl halogenoformate is carried out in the presence of a basic agent such a a alkyl or the reaction between the carbamate and the amino alkanol is performed in water or in mixture of water and a solvent the chlorinating agent is thionyl phosphorus phosphorus phosphorus or Some of the intermediates used in the above process are new and form the subject matter of Patent Application 7 3 ost of the starting of general formula II are already described in the literature see U3P Acta 1059 and 33 4054 The other starting nay be prepared according to similar methods starting from a cyclopropyl ketone and condensing the latter with reducing the oxime thus produced with sodium and an alkanol or with a mixed recovering the cyclopropyl which may be alkylated by condensation with a lower alkyl aldehyde and reducing the Schiff base by means of an The isocyanates and thiocyanates of general formula III may be prepared according to the process described by Sefken J Liebigs Annalen der Chemie 562 The following examples illustrate the invention EXAMPLE 1 and its neutral fumarate Step urea A solution made from g of amine in 30 ml tetrahydrofuran is added dropwise to a solution of 13 g of isocyanate in ml tetrahydrofuran while the inner temperature from to the reaction mixture is kept at room temperature for the solution is evaporated to dryness and the dry weighing is used as such for the next step of the For a sample of the crude urea is recrystallised from The urea occurs as white crystals melting at with Step 25 g of crude urea obtained by step are suspended in 150 ml of water and heated under reflux for 2 After allowing the temperature of the to return to room the aqueous solution is extracted th ethe e a ueous has is se ara e a The resulting precipitate is separated by washed with water and g of are thus melting at A mixture of the latter with urea gives a decrease of the melting For the product is further purified by means of at under a pressure of The purified product melts at The elemental the and spectra confirm the structure of the obtained Step neutral fumarate 12 g of obtained by step are dissolved in 60 ml To a solution made from g fumaric acid in 15 ml ethanol is added The mixture is allowed to stand over The precipitate is isolated by washed with ethanol and g of neutral fumarate are thus Its melting point is Beer stallisation from 50 ml ethanol gives g of an analytical sample whose melting point remains EXAMPLE II and its neutral fumarate Step thiourea g isothiocyanate dissolved in 20 ml tetrahydrofuran are added dropwise to a solution of 9 g of in 70 ml The reaction mixture is kept at a temperature of from to consisting essentially of recovered and used without any further for the next step of the Step crude thiourea obtained by step is in 100 sal of water and dissolved by After complete the aqueous phase is extracted with the organic phase is The aqueous solution is alkaline by adding an excess of sodium hydroxide oily fraction separates which is then extracted with The organic solution is washed with dried sodium filtered and evaporated to The crystallised residue is purified by dissolving it in the amount of hot By allowing the solution to stand in a cool 6 g of melting at are Step neutral fumarate g of 2 iazoline are dissolved in 20 ml g of fumaric acid dissolved in 20 ml are then The mixture is stirred for 2 The precipitate of the fumarate is separated by washed with ethanol and g of fumarate are thus which may be purified by recrystallisation from g of purified fumarate melting at 195eC are EXAMPLE XXI and its acid fumarate Using the procedure described in Example I step starting from 6 g of amine and g of of urea melting at are The latter is cycllsed using the procedure of Example I step and gives Its melting point is about and its boiling point BP By adding an solution of fumaric acid fumarate is formed which is then puri by recrystallisation from 10 EXAMPLE IV g of amine are dissolved in 30 ml of g of imidazoline are added to this solution and the reaction mixture heated at during the course of 8 hours under an inert After allowing the reaction mixture to return to ambient dimethylformamide is distilled off and the residue is recrystallised from 25 ml ethyl g of imidazoline melting at with sition are The hydriodide is converted into the base by The imidazoline melts at EXAMPLE V Using the procedures given in Example the following compounds are obtained DEFINITIONS OP THE MELTING POINT OP THE CHARACTERISTICS OP KELTING POINT T SUB3TITUE TS INTERMEDIATE UREA THE OXAZOLIHE SALT OP THE O A n cyclo H 0 1 propyl 0 zero EXAMPLE VI Step cyclopropane A mixture from 49 g methyl 175 ml pyri and 32 g hydroxylamine hydrochloride is heated on a water hath for 3 Afte return to room the clear solution is distilled off under reduced The oily residue is then poured in 100 ml water and kept under stirrin for one The crystals are washed with water and dried in an oven g cyclopropane are thus After recry 10 tallisation heptane the pure product melts at The yield amounts Step ethylamine 45 g of cyclopropane are suspended in 170 tetrahydrofuran with strong After few the dissolution is comp 15 and to the clear solution g aluminium lithium hydride in suspension into a mixture of ether and tetrahydrofuran are The whole is heated to 3 hour3 then let to return to room the excess of reagent is cautiously destroyed by adding water then dilute hydrochloric acid until The acidic solution is 20 then made strongly basic by adding potash and extracted many times with The organic phases are washed with with a solution of sodium carb t nate then with dried on sodium sulphate and distilled off EXAMPLE VII trans trans isomers Using the procedure of Example starting from ketone isomers obtained according to following compounds were obtained oxime of ketone 120 amine crude urea oxazoline melting at after recrystallisation from The oxazoline dissolved in the stoichiometric amount of hydrochloric acid is converted into its hydrochloride which is recovered after distillation to EXAMPLE VIII Using the procedure of Example VI and starting from methyl the following compounds are produced cyclopropane 2p ethylamine n2J hydrochloride N chloroeth urea melting at The compound is purified by distillation under reduced pressure It is converted into the hydrochloric acid addition salt by means of the stoichiometric amount of hydrochloric acid and evaporation of the solvent to EXAMPLE IX and its hydrochloride Using the procedure of Example VI and starting from the following compounds are obtained t propane melting at propane boiling at under pressure crude urea melting at Its hydrochloride is obtained after solution in the stoichiometric amount of hydrochloric 13 one is according to the process of France 161 EXAMPLE X amino and its hycrochloride Using the procedure disclosed in VI and starting from lcycloprop methyl ketone prepared according to France 1 the following compounds are obtained amine hydrochloride MP urea MP 1 amino melting at Its hydrochloride is obtained according to the above described XI and its acid fumarate Step amine 4 g amine are dissolved in 30 ml tetrahydrof To this one adds a solution of 1 g acetaldehyde in 10 ml The reaction mixture is kept under stirring for 30 then the precipitate of Schiff base is washed many times with water and dried under The crude Schiff base is further redissolved in 40 ml methanol and a solution of sodium borohydride in methanol water is added After completion of this the mixture is heated to reflux for then placed in a cooled place until return to about 30 ml ice water are then added and the mixture is stirred for 30 The precipitate is separated by decanting it and taken up in 20 ml isopropyl The organic solution is washed with o colorized with activated filtered and The solvent is further evaporated off under reduced g amine are thus obtained The crude amine is purified by converting it into its hydrochloride melting at after recrystallisation from Step clop ropy lme th N urea Using the procedure as at step of Example is obtained with an about quantitative It is without further purification for the next step of the step and its acid fumarat Using the same procedure as in step of Example I is obtained as a boiling at under a pressure of After solution in ether and addition of an ethanolic solution of fumaric crystalls of fumarate are isolated and It occurs as white very soluble in melting at EXAMPLE XII and its acid fumarate Operating as in XI and starting and the following compounds are obtained lme urea rop lme oxazoline and its acid fumarate melting at after recrystallisation from EXAMPLE XIII and its hydrochloride Using the same procedure as in VI and starting from cyclopropyl ketone the following compounds are produceds of cyclopropyl ketone urea oxazoline after recrystallisation from The hydrochloride is obtained by additon of the stoichiometric amount of hydrochloric The starting cyclopropyl ketone is obtained according to the process described by France 161 EXAMPLE Ste a phenyl To a solution of g in g of and 1500 ml 234 g phenyl are added under vigourous The reaction is cooled in order tha the inner temperature lies between 5 and After completion of the addition which lasts about 30 the cooling is withdrawn and the reaction mixture let to revert to room After standing two hours at about the precipitate is separated by washed with water 307 g of phenyl thus recovered a yield of The compound melts at For analytical a is recrystallised It at Step urea In a flask 100 g g ethanolamine and 450 water are successively The mixture is heated to reflux for 2 After return to room th aqueous solution is extracted with The chloroformic washings are washed with dried The solvent is distilled off and the dry residue is made into a paste in 500 ml The insoluble matter is recovered by fil again made into a paste with ether and 67 g urea are The yield The pure compound melts at Step g of urea obtained in preceding step are added to a solution of ml thionyl chloride in 160 ml The mixture is stirred for 30 while maintaining the inner temperature between and The solvent and excess of reagent are distilled off under vacuum at a temperature below The dry residue consisting o crude urea is suspended in 100 stl water and heated to reflux for 30 After standing in a cool the mixture is extracted with 20 ml ether three The ether phases are discarded and the aqueous solution is made basic by adding 10 ml concentrated The oxazoline precipitates and is extracted with The ether solution is washed with dried over sodium filtered and evaporated to g are thus obtained a yield of After recrystallisation of an analytical sample from amino hexane the melting point of pure oxazoline is The compound is identical with that obtained according to the procedure of Example Using the preceding procedure but using instead of is obtained after Its fumarate melts at Similarly using instead of amino 7 is EXAMPLE XV Pharmacological study of the compounds Acute The acute toxicity has been determined on mice weighing between 20 and 22 g by intraperitoneal and oral administration of increasing The compounds of formula I have low The average lethal doses range from 100 to 500 upon intraperitoneal administration and from 250 to 2000 upon oral Activity on The compounds of formula I have been administered intravenously to groups of dogs previously After a increase of the blood a significant decrease of the blood pressure occurs ranges from 12 to 30 at a dose of from 100 to The compounds of formula X possess strong At a dose as as 100 they reduce the heart rate by compounds of formula have little effect on heart Only high doses induce a significant The compounds of formula X have a effect on the dose of 300 γ decreases the blood pressure of said dogs for more than one insufficientOCRQuality

Claims

43749/2 CLAIMS ; l) Substituted cyclopropylmethylamines of the general formula wherein and R2, which are the same or different, each represents a hydrogen atom, a lower alkyl radical or a cyclopropyl radical optionally substituted with one or more lower alkyl radicals 4.12.1973 - R' is a lower alkyl radical for under- , _ Ί lined - R3 is a hydrogen atom or a lower alkyl radical meanings of sub- - A is an oxygen atom, a sulphur atom or an stituents inimo -NH- radical - n is 0, 1 or 2 and their acid addition salts with a physiologically acceptable mineral or organic acid. 2) Compounds according to Claim 1 in their optically-active form. 3) A compound according to Claim 1 of the formula ; wherein ^ and R2, which are the same or different, represent each a hydrogen atom, a lower alkyl radical or a cyclopropyl radical. A is an oxygen atom, a sulphur atom or an imino radical and n isO, 1 or 2. 43749/2 2- 4) 2- (Dicyclopropylmethyl) ^femino oxazoline and ^ its fumarate. 5) Compounds of formula I in Claim 1 and their pharmaceutically acceptable acid addition salts and optical isomers, substantially as described herein with reference to the Examples . 6 ) A process for the manufacture of compounds of formula I in Claim 1 in which A is oxygen or sulphur, wherein a compound of the formula : in which R' , R^ , R2 , Rg and n' have the meanings given in Claim 1 is reacted with a ω-halogeno alkyl isocyanate or isothiocyanate having the formula : A%= C = N - (CH2)n„ - Hal III wherein A' is an oxygen or sulphur atom, Hal is a chlorine or bromine atom and n" is an integer of from 2 to 4, to form a disubstituted urea or thiourea of formula : )n„ - Hal IV which latter is cyclised by heating to form a compound of formula I , in which A is as defined above , and , if desired , the compound of formula I thus obtained is converted by reaction into- a mineral or organic acid , into an acid addition salt or resolved into its optical isomers by reaction with an optically-active acid. 43749/2 7) A process for the manufacture of compounds of formula I in which A is an inimo group, wherein a compound of formula II in Claim 6 in which R* , R^, R2 , Rj and n1 have the meanings given in Claim 1 is reacted with a cyclic S-methyl isothiourea of the formula wherein n is 0, 1 or 2, and, if desired, the compound of formula I thus obtained is converted by reaction with a mineral or organic acid, into an acid addition salt or resolved into its optical isomers by reaction with an optically-active acid. 8) A process for the manufacture of compounds of formula I in Claim 1 and having the formula in which the substituents are as defined in Claim 1 wherein a cyclopropylamine of formula II in Claim 6 is reacted with an aryl halogeno formate of the formula in which Hal is fluorine or chlorine and Ar is a phenyl radical optionally substituted by one or more radicals of electrophilic character to produce a carbamate of the formula 43749/2 wherein R * , R^ , R2 , 3 , A-E. and n ' are as defined in Claim 1 the carbamate of formula VI i s condensed with an aminoalkanol of formula (CH - OH VJI 2'n' wherein n" is an integer f om 2 to 4 form a hydroxyalkyl urea of formula which is converted by reaction with an halogenat ing agent into the corresponding ω-halogenoalkyl urea of formula *1 ° ( « )n, C - N - C - M {CEjn„ - Hal IV ¾ R3 and the latter is heated to form a compound of formula I wherein A is oxygen . 9 ) A process according to claim 6 wherein the condensation between a cyclopropylamine of general formula II with an isocyanate or isothio-cyanate of general formula III is carried out in an inert solvent such as a cyclic or non Qyvli" ether, a trialkylamine, an aromatic hydrocarbon, a lower alkyl alkanoate or a cycloalkane . 10 ) A process according to Claim 6 wherein the cyclisation of the urea or thio urea of general formula IV is carried out by heating in an aqueous medium. 43749/2 IX) A process according Claim 6 wherein the cyclisation ψ. is performed by heating at a temperature between 50 and 120*C. 12} A proc ss according to Claim 7 wherein the condensation between the cyclopropyXamine of general formula II and a cyclic S-methyl isothlo tirea of formula V is effected by heating from 50 to 150*C in a polar solvent. 13) A process according to Claim 8 wherein the aryl halo-genoformate is an aryl chloroforiate. 14} A process according to Claim 8 wherein the aryl radical of the aryl halofomate is a phenyl radical or a phenyl radical substituted by one or more nitro groups. 15) A process according to Claisi 8 wherein the condensation between the aryl halogenoformate and th cyclopropy amne of formula XX is carried out in the presence of a basic agent. 16} A process according to Claim 8 wherein the reaction between the carbamate of formula VI and the aminoalkanol of formul VII is performed in an aqueous medium. 17) A process according to Claim 8 wherein the halogenating agent is selected from thi&yl chloride, phosphorus chloride, phosphorus oxychloride and iJ-bromoacetamide. 18) Processes for the preparation of compounds of formula I in Claim 1, substantially as described herein with reference to the Examples. 19) Pharmaceutical compositions comprising as active ingredient at least one 1 in admixture with a pharmaceutically acceptable non toxic inert carrier* 20. Pharmaceutical compositions according to Claim 19 in a form suitable for oral, parenteral, sublingual or rectal administration*

1. Pharmaceutical compositions according to Claims 9 and 2Q containing as active ingredient from 1.5 eg 5 mg per unit dosage of a compound of Claim 1.